. Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nat Chem Biol. 2007 Jun;3(6):331-8. PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. Rapamycin has been a crucial pharmacological tool for positively regulating autophagy through the mTOR (mammalian Target-of-Rapamycin) kinase pathway. Earlier studies with this compound by the Rubinsztein group provided the initial evidence supporting autophagy enhancement as a therapeutic strategy against the toxicity of misfolded proteins in aging-related neurodegenerative diseases. In this new report, Sarkar and colleagues expand the horizons for autophagy modulation as therapy by identifying a set of novel autophagy-enhancing agents (SMERs) that promote the clearance of mutant huntingtin and α-synuclein aggregates in mammalian cell and Drosophila models. These agents potentiate the aggregate-clearing effects of rapamycin but, curiously, their actions are not mediated through mTOR, raising the exciting prospect that novel points of regulation within the autophagy pathway are yet to be discovered. The three SMERs described appear to act at the stage of autophagosome formation rather than on later digestive steps after the autophagosome fuses with a lysosome. These tantalizing data beg now for both in vivo validation in animal models of these diseases, which undoubtedly is in progress, and for studies on the molecular targets of these agents. In the second paper by Hughes and colleagues, it is noteworthy that at least a few of the suppressor genes have connections to autophagy.

    Autophagy enhancement holds considerable promise for remediation in Alzheimer disease, where autophagy pathology in neurons is especially florid and may involve defects in autophagosome clearance. The defects in autophagy in AD have, in turn, been linked to Aβ and tau accumulation as well as neurodegeneration. If, as is suspected, the later steps in autophagy, such as autophagosome-lysosome fusion and substrate proteolysis, are impaired in AD, therapy may require a different type of autophagy enhancement than that offered by the first generation of SMERs, which target the early autophagy steps. If autophagosome clearance is impaired, strongly inducing autophagosome formation in AD may exacerbate an already massive neuronal build-up of “intermediate” autophagic compartments, some of which are able to generate Aβ (Yu et al., 2005) or possibly other toxic metabolites. In diseases where the autophagic pathway may be normal or sluggish but not defective, as seems to be the case in Huntington disease models, pharmacologically ramping up the sequestration of misfolded proteins would be expected to promote more rapid digestion, as observed.

    In AD, the attention may need to be directed toward increasing the efficiency of lysosomal-mediated substrate digestion. Whether or not these considerations turn out to be relevant, there is no downside to extending these exciting drug screening efforts to identify enhancers of every step in the autophagy pathway for future dissection of the pathway and possibly for therapy.

    View all comments by Ralph Nixon

Make a Comment

To make a comment you must login or register.